Adolescence is a critical neurodevelopmental period that is associated with dramatic increases in rates of substance use. Identifying the pathways to substance use and its effects on child and adolescent development is critically important, as the effects of substance use during ongoing maturation likely have long-lasting effects on brain functioning and behavioral, health, and psychological outcomes. This Research Project Site application from the University of Michigan and University of Florida is in response to RFA-DA-15-015, as part of the ABCD-USA Consortium (9/13) to prospectively determine the neurodevelopmental and behavioral effects of substance use on children and adolescents. A representative community sample of 975 9-10 year olds with enrichment for high-risk will be recruited as part of this application, contributing to the sample of 11,111 to be collected from 11 total sites across the ABCD-USA Consortium. All participants will undergo a comprehensive baseline assessment, including state-of-the-art brain imaging, comprehensive neuropsychological testing, DNA, and extensive assessment of substance use patterns, behavioral, psychological and social functioning. These comprehensive assessments will repeat at 2-year follow-up intervals, with intermediate assessments of functioning and substance use at 6-month intervals. These Consortium-collected data obtained during the course of this project will elucidate: 1) the effects of substance use patterns on the adolescent brain; 2) the effects of substance use on behavioral and health outcomes; 3) the bidirectional relationship between psychopathology and substance use patterns; 4) the effects of individual genetic, behavioral, neurobiological, and environmental differences on risk profiles and substance use outcomes; and 5) the gateway interactions between use of different substances. This Research Project focuses on risk and protective factors influencing trajectories of substance use and associated behaviors. Our emphasis is on: externalizing and internalizing phenotypes, both as core nonspecific risk factors for problem substance use and as important co-occurring outcomes of substance use; contextual factors (including sociodemographic, family and social influences) as risk and protective influences on the co-development of brain, substance use and psychopathology; and sex as a moderator of these relationships. We use novel methods for linking these factors to brain maturation. We address three aims: 1) At age 9-10, identify the neurofunctional and contextual factors influencing individual differences in externalizing and internalizing phenotypes prior to substance use; 2) Identify baseline neurofunctional predictors and contextual moderators over time of early (before age 14) substance use initiation; and 3) Characterize the developmental relationship between brain maturation, externalizing/ internalizing symptomatology, context, and substance use. This work will uncover neural correlates of distinct etiological pathways underlying adolescent substance use and identify temporal relationships between brain maturation, substance use and psychopathology.